1-alkylidene-benz[b] cycloalkanes



United States Patent 3,26%,125 1-ALKYLIDENE-BENZ[F0]CYCLQALKANES William Laszlo Bencze, New Providence, NJ, assignor to Qiba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed June 25, 1962, Ser. No. 205,082 Claims. (Cl. 260-290) This is a continuation-in-part application of my application Serial No. 137,001, filed September 11, 1961, now U.S. Patent No. 3,157,665.

The present invention concerns l-methylene-benz[b] cycloalkane compounds, which have in the 2-position, i.e. the position adjacent to the carbon atom carrying the methylene group, a pyridyl group and an aliphatic radical. More especially, the present invention relates to compounds of the formula:

C Py

in which Ph stands for a 1,2-phenylene (o-phenylene) radical, Py is a pyridyl group, R stands for an aliphatic radical, and the group of the formula (C H in which the letter r: stands for a Whole number from one to seven, is an alkylene radical and separates the 1,2- phenylene radical Fit from the carbon atom carrying the pyridyl group by Py and the aliphatic radical R by one to three carbon atoms, or salts thereof, as well as N-oxides, salts of N-oxides or quaternary ammonium derivatives of such compounds, and process for their preparation.

The 1,2-phenylene (o-phenylene) radical Ph stands for an unsubstituted 1,2-phenylene or a substituted 1,2-phenylene radical. Substituents attached to the latter are, for example, aliphatic groups, such as lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl and the like, substituted aliphatic groups, e.g. trifiuoromethyl and the like, hydroxyLetherified hydroxyLparticularly loweralkoxy,e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, as well as lower alkenyloxy, e.g. allyloxy, Z-methyl-allyloxy and the like, lower alkylenedioxy, e.g. methylenedioxy and the like, lower cycloalkyloxy, e.g. cyclopentyloxy, cyclohexyloxy and the like, esterified hydroxyl, especially halogeno (representing hydroxyl esterified with a hydrohalic acid), e.g. fiuoro, chloro, bromo and the like, etherified mercapto, particularly lower .alkylrnercapto, e.g. methyl-mercapto, ethyhnercapt-o and the like, nitro, amino, especially primary amino, as well as secondary amino, such as N-lower alkyl-arnino, eg. N-methylamino, N-ethylamino and the like, tertiary amino, such as N,N-dilower alkyl-amino, e.g. N,N-dirnethylamino, N-ethyl-N- methylamino, N,N-d iethylamino and the like, or N-acylamino, in which acyl is the .acyl radical of an organic carboxylic acid, eg acetic, propionic, pivalic acid and the like, a substituted aliphatic, particularly lower alkanoic, acid, e.g. cyclohexylacetic, 3-cyclopentylpropionic. dichloroacetic acid .and the like, a carbocyclic aryl carboxylic acid, e.g. benzoic, 4-methoXy-benzoic, 3,4,5-trimethoxybenzoic, 3,4-dichloro-benzoic, 3-N,N-dimethylamino-benzoic acid and the like, a carbocyclic aryl-aliphatic, especially a monocyclic carbocyclic aryl-loWer alkane carboxylic acid or a monocyclic carbocyclic aryl-lower alkene carboxylic acid, e.g. phenylacetic, cinnamic acid and the like, or a heterocyclic, particularly a monocyclic heterocyclic aryl carboxylic acid, e.g. nicotini-c, isonicotinic, furoic acid and the like, or any other suitable organic carboxylic acid.

Substituted 1,2-phenylene groups are, for example, lower alkyl-l,2-phenylene, e.g. methyl-1,2-phenylene (such as 3-methyl-l,2-phenylene, 4-methyl-1,2-phenylene, 4,5-dimethyl-1,2-phenylene and the like), ethyl-1,2-phenylene 32%,125 ?atented Aug. 10, 1965 (such as 4-ethyl-1,2-phenyleue and the like), n -propyl-l,2- phenylene (such as 4-n-propyl-1,2-phenylene and the like), isopropyl-1,2-phenylene (such as 3-isopropy1-1,2-phenylene and the like), or any other analogous lower alkyl-1,2- phenylene radical, trifiuoromethyl-l,2-phenylene (such as 4-trifluorornethyl-1,2-phenylene and the like), hydroxy- 1,2-phenylene (such as B-hydro-xy-l,2-phenylene, 4-hydroxy-1,2-phenylene and the like), lower alkoxy-1,2-phenylene, e.g. methoxy-LZ-phenylene (such as 3-methoxy-1,2- phenylene, 4-methoxy-1,2-phenylene, 3,4-dimethoxy-l,2- phenylene, 4,5-dimethoxy-1,2-phenylene and the like), eth- OXy-LZ- henylene (such as 3-ethoxy-1,2-phenylene, (4- ethoxy-1,2-phenylene, 3,6-diethoxy-1,Z-phenylene and the like), n-propyloxy-1,2-phenylene (such as 4-n-propyloxy- 1,2-phenylene and the like), isopropyloxy-l,Z-phenylene (such as 3-isopropyloxy-1,2-phenylene and the like), n-butyloXy-1,2-phenylene (such as 4-n-butyloxy-1,2-phenylene and the like), or any other analogous lower 'alkoXy-l,2- phenylene radial, lower alkenyloxy-l,2-phenylene, e.g. allyl0xy-l,2-phenylene (such as 3-allyloXy-1,2-phenylene, 4- allyloXy-l,2-phenylene and the like), or any other analogous lower .alkenyloxy-1,2-phenylene radical, lower alkylene-dioxy-1,2-phenylene, e.g. methylenedioxy-l,2-phen ylene (such as 3,4-methylenedioxy-1,2=phenylene and the like), or any other analogous lower alkylenedioxy-LZ- phenylene radical, halogeno-1,2-pheny1ene, e.g. fluor0-1,2- phenyleue (such as 3-flu0ro-l,2-phenylene, 4-ilu0ro-l,2- phenylene and the like), chloro-1,2-phenylene (such as 3-chloro-1,2-phenylene, 4-chloro-l,2-phenylene, 4,5-dichloro 1,2-phenylene, 3,4,5,6-tetrachloro-1,2-phenylene and the like), br0mo-1,2-phenylene (such as 4-bromo-l,2- phenylene, 3,6-dibromo-1,2-phenylene and the like), or any other analogous halogeno-1,2-phenylene radical, lower alkylmercapto-1,2-phenylene, e.g. methylmercapto-LZ- phenylene (such as 4-rnethylmercapto-1,2-phenylene and the like), ethylmercapto-1,2-phenylene (such as 3-ethylmercapto-1,2-phenylene and the like), or any other analogous lower alkyl-rnercapto-l,2-phenylene radical, nitro- 1,2-phenylene (such as 3-nitro-1,2-phenylene, 4-nitro-1,2- phenylene and the like), amino-1,2-phenylene (such as 3-amino-l,2-phenylene, 4-.amino-1,2-phenylene and the like), N-lower alkyl-amino-l,2-phenylene, e.g. N-methylamino-1,2-phenylene (such as 3-N-methylamino-1,Z-phenylene, 4-N-methylamino-1,2-phenylene and the like), N-ethylamino-l,2-phenylene (such as 3-N-ethylamino-l,2- phenylene and the like), or any other analogous N-lower .alkylamino-l,2-phenylene radical, N,N-di-lower alkylamino-1,2-phenylene, e.g. N,N-dimethylamino-1,2-phenylone (such as 3-N,N-dirnethylamino-1,2-phenylene, 4-N,N- dimethylamino-l,Z-phenylene and the like), N-ethyl-N- methyl-amino-l,Z-phenylene (such as 4-N-ethyl-N-methylamino-1,2-phenylene and the like), N,N-diethylamino- 1,2-phenylene (such as 4-N,N-die'thylamino-1,2-phenylene and the like), or any other N,N-di-lower alkyl-amino-l,2- phenylene radical, N-acyl-amino-l,Z-phenylene, such as N-lower alkanoyl-amino-l,2-phenylene, e.g. N-acetylamino-1,2-phenylene (such as 4-N-acetylamino-1,2-phenylene and the like), N-pivaloylamino-l,Z-phenylene (such as 4-N-pivaloylamino-1,2-phenylene and the like), as well as N-benzoylamino-1,2-phenylene (such as 4-N-benzoylamino-1,2-phenylene and the like), or any other analogous N-acyl-amino-1,2-phenylene radical, or any equivalent substituted 1,2-phenylene radical.

A pyridyl group Py represents an unsubstituted pyridyl radical, e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl, .as well as a substituted pyridyl radical which contain lower alkyl, e.g. methyl, ethyl, n-propyl, n-butyl and the like, lower alkoxy, e.g. methoXy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or any other suitable substituent attached to any of the positions available for substitution.

The group R, attached to the carbon atom carrying the pyridyl group, represents an aliphatic radical, particularly lower alkyl having preferably from one to four carbon .atoms, especially methyl, as well as ethyl, n-propyl, isopropyl, n-butyl, secondary butyl and the like. It may also stand for a substituted aliphatic radical, for example, a carbocyclic aryl-aliphatic group, such as monocyclic carbocyclic aryl-lower alkyl, particularly phenyl-lower. alkyl, e.g. benzyl, l-phenylethyl, Z-phenylethyl and the like, or phenyl-lower alkyl, in which phenyl is substituted,

.for example, by lower alkyl, e.g. methyl, ethyl, isopropyl and the like, lower .alkoxy, e.g. methoxy, ethoxy and the .like, halogeno, e.g. fluoro, chloro, bromo and the like, or

ethylene, 1,1-propylene, 1,3-propylene, 1,3-butylene, 2,3-'

butylene, 1,1-isobutylene and the like. In view of the fact that the 1,2-phenylene radical and the carbon atom carrying the pyridyl group and the aliphatic radical are separated by one to three, particularly by two carbon atoms, the compounds of the present invention are, therefore, above all 1 methylene l,2,3,4 tetrahydro-naphthalene compounds, as well as l-methylene-indane or l-methylene-benzosuberan compounds, which have in the 2-position, i.e. in the position adjacent to the carbon atom carrying the methylene group, a pyridyl group and an aliphatic radical.

Salts of the compounds of this invention are particularly pharmaceutically acceptable, non-toxic acid addition salts, primarily those with'inorganic acids, eg hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids, as Well as with organic acids, such as organic carboxylic acids, e.g. acetic, glycolic, maleic, hydroxymalei-c, malic, tartaric, citric, salicylic acid and the like, or organic sul- ,fonic acids, eg methane sulfonic, ethane sulfonic, 2-

.N-oxides and the salts, particularly the pharmaceutically acceptable, non-toxic acid addition salts of such N-oxides with the above-mentioned inorganic and organic acids.

Quaternary ammonium derivatives of the compounds .of this invention are those with reactive esters formed by hydroxylated compounds and strong acids, such as those .with lower alkyl halides, e.g. methyl, ethyl, propyl or isopropyl chloride, bromide or iodide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alklane sulfonates, e.g. methyl or ethyl methane sulfonate or ethane sulfonate and the like, lower alkyl monocyclic carboxylic aryl sulfonates, e.g. methyl p-toluene sulfonate and the like, phenyllower alkyl halides, e.g. benzyl, l-phenylethyl or 2-phenylethyl chloride, bromide or iodide and the like, or any other suitable reactive ester. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and the quaternary ammonium salts with organic or inorganic acids other than hydrohalic, sulfuric and sulfonic acid, such as those mentioned above.

The compounds of the present invention may be in the form of racemates or optically active antipodes.

The compounds of this invention inhibit certain functions of the adrenal cortex which is manifested in a strong and prolonged decrease of the excretion of hydro cortisone (compound ,F) and corticosterone (compound B), and a less pronounced and shorter decrease of the secretion of ll-desoxy-l7a-hydroxycorticosterone (compound S), which elfects are accompanied by an immediate increase in the secretion of desoxy-corticosterone (DOC, cortexone); these effects indicate a preferential inhibition of the lll3-hydroxylase enzyme system.

The compounds ofthe present invention having these specificadrenal cortex inhibiting effects can, therefore, be used as diagnostic tools for the determination of the functioning of the pituitary gland, as well as in the'treat- ,ment of conditions causing adrenal corticalhyperfunction, such as Cushings syndrome, primary aldosteronism,

secondary aldosteronism and the like. Furthermore, the preferential inhibition of certain functions of the adrenal cortex makes the compounds of this invention useful as experimental tools in the study of biosynthetic pathways of corticoid synthesis. a V

The compounds of the formula Cfl -Cflf in which Ph' stands for 1,2-phenylene, lower alkyl-1,2- phenylene, hydroxy-1,2-phenylene, lower. alkoxy-l,2- phenylene, halogeno-LZ-phenylene, nitro 1,2-phenyl-ene or amino-1,2-phenylene, Py is pyridyl, particularly 3- pyridyl or 4-pyridyl, R is lower alkyl, particularly methyl, and the, pharmaceutically acceptable, nontoxic acid addition salts of such compounds, represent a preferred group of compounds, which show especially outstanding adrenal inhibiting effects of the above-mentioned type.

The new compounds of this invention may be used in the form of compositions for oral or parenteral use which .contain the new compounds of this invention in admixture with an organic or inorganic, solid or liquid carrier. For making up such compositions there canbe employed substances which do not react with the new compounds, such as water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, vegetable oils,

benzyl alcohols, gums, propylene glycol, polyalkylene glycols, or any other carrier used for such preparations.

The latter may be in the solid form, for example, as

capsules, tablets, drageesv and'the like, or in liquid form,

for example, as solutions, suspensions, emulsions and the n 2n) \R v in which Ph, Py, R and (C,, H have the previouslygiven meaning, ora salt, an N-oxide or a salt of an N- oxide thereof, by dehydration, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, introducing a substituent into the carbocyclic aryl, e.g. the 1-,2-phenylene, portion of a resulting compound, and/ or, if desired, converting a substituent attached tothe carbocyclic aryl, e.g. the 1,2-phenylene, portion of a resulting compound intoanother. substituennandlor, if desired, converting a resulting compound into an N-oxide thereof of a quaternary ammonium derivative thereof, and/or, if desired converting a resulting compound or an N-oxide thereof into a salt thereof, and/ or, if desired, converting a resulting quaternary ammonium compound into another quaternary ammonium compound, and/ or, if desired, separating a resulting mixture of isomers into the single isomers.

The elimination of the elements of water from the starting material may be achieved according to known dehydration methods, for example, by heating, or preferbly by treatment with a dehydrating agent, advantageously an acidic dehydrating agent. Suitable dehydrating agents are, for example, mineral acids, e.g.

hydrochloric, hydrobromic, sulfuric, phosphoric acid and the like, anhydrides of mineral acids, e.g. phosphorus pentoxide and the like, mixtures of inorganic acids and their anhydrides, e.g. polyphosphoric acid and the like, organic acids, such as organic carboxylic acids, e.g. acetic acid and the like, as well as anhydrides thereof, e.g. acetic acid anhydride and the like, or organic sulfonic acids, e.g. p-toluene sulfonic acid and the like. Other useful acidic dehydrating reagents are certain salts of Weak organic bases with strong inorganic acids, e.g. pyridine hydrochloride, quinoline hydrochloride and the like, or

any other suitable acidic dehydrating reagent, as well as mixtures of such reagents, for example, the mixture of a'mineral acid, e.g. hydrochloric acid and the like, and a suitable organic acid, e.g. acetic acid and the like. Dehydration may be achieved at room temperature, but is more efficiently accomplished at elevated temperatures. The acidic dehydration reagents may simultaneously serve as diluents; if necessary, other inert solvents may be added to ensure a complete solution. Furthermore, the reaction may be carried out in a closed vessel, and/or in the atmosphere of an inert gas, e.g. nitrogen.

The 1-methyl-benz[b]cycloalkan-l-ol compounds, particularly the compounds of the formula HO CH3 O Py Pg n Zn) R in which Ph, Py, R and (C,,H2n)- have the previously-given meaning, salts, N-oxides or salts ofN-oxides thereof, which are used as the starting materials in the above dehydration procedure, are new and are intended to be included within the scope of this invention. Particularly useful as starting materials are the compounds of the formula HO CH5 C Py t CHZ-CHQ in which Ph', Py', R and R have the previously-given meaning, or the acid addition salts thereof.

The starting materials may be prepared, for example, by reacting a benz[b]cycloalkan-1-one, which carries a pyridyl group and an aliphatic radical attached to the carbon atom-adjacent to the carbonyl group, particularly a compound of the formula in which Ph, Py, R and (C H have the previouslygiven meaning, with a methyl organo-metallic reagent, particularly a reagent of the formula 6 in which M stands for the positively charged ion of certain metals of IA-group of the Periodic System or, more particularly, for the positively charged ion of the formula Met-Hal in which Met represents certain divalent metals of the llA-group and the llB-group of the Periodic System, and Hal stands for halogeno, and, if desired, converting a resulting salt into the free compound or into another salt and/ or, if desired, introducing into the carbocyclic aryl, e.g. 1,2-phenylene, portion of a resulting compound a substitutent, and/ or, if desired, converting in a resulting compound a substituent attached to the carbocyclic aryl, e.g. 1,2-phenylene portion, into another substituent, and/or, if desired, converting a resulting compound into a salt thereof, an N-oxide thereof or a salt of an N-oxide thereof.

The ion M represents primarily the positive ion of an alkali metal, such as sodium, or particularly lithium, or, more especially, the positive ion of the formula Mg-Hal in which Hal represents halogeno, e.g. chloro, bromo, iodo and the like. Both types of reagents are used under similar conditions; preferably, the alkali metal compound or the Grignard reagent is prepared separately and is then reacted with the ketone. The solvent used in the preparation of the reagent, especially the Grignard reagent, for example, a di-lower alkyl ether, particularly diethyl ether, may be diluted or replaced by another solvent, for example, by another ether, such as a monocyclic carbocyclic aryl lower alkyl ether, e.g. anisole and the like, a bis-monocyclic carbocyclic aryl ether e.g. diphenyl ether and the like, a cyclic ether, e.g. tetrahydrofuran, p-diox-ane and the like, an organic base, e.g. pyridine, N-methyl-morpholine and the like, a monocyclic carbocylic aryl hydrocarbon, e.g. benzene, toluene, xylene and the like, or an aliphatic hydrocarbon e.g. pentane, hexane and the like, or any other suitable solvent or solvent mixture. The reaction may be carried out while cooling, at room or at an elevated temperature; if necessary, the atmosphere of an inert gas, e.g. nitrogen, may be required, particularly when an alkali metal reagent is used. The resulting reaction mixture may be worked up according to known methods. Thus, a complex resulting from the reaction of the ketone starting material with a Grignard reagent may be broken, for example, by adding a weak acid, such as an aqueous solution of ammonium chloride and the like, to the reaction mixture, and the desired product may then be isolated according to standard procedures.

The intermediates used in the above reaction may be prepared according to known methods; for example, the salt of a functional derivative of a pyridylaace-tic acid, particularly an alkali metal salt of a compound of the formula in which Py has the previously-given meaning, R stands for hydrogen or an aliphatic radical, and R represents a functionally converted carboxyl group, is reacted with a reactive ester of a phenyl-lower alkanol, particularly with a compound of the formula tional derivative of such carboxyl-ic acid, particularly a compound of the formula:

in which Ph, Py, R, and the group of the !Eormula (-C H have the previously-given meaning, and R stands ifiOl a carboxyl group or a functionally converted carboxyl group, or a salt, an N-oxide or a salt of an N-oxide of such compound, is treated with a strong Lew-is acid ring closing reagent, and, if necessary, in a resulting compound having a hydrogen attached to the carbon atom carrying the pyridyl group, such hydrogen is replaced by an aliphatic radical.

The several steps of the above procedure are carried out accordingto known methods. A salt of a functional derivative of a pyridyl-acetic acid is primarily an alkali metal salt, e.g. lithium, sodium, potassium and the like. salt; the latter may be prepared, for example, by treatment with an alkali metal, e.g. sodium and the like, an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal hydride, e.g. sodium hydride and the like, an alkali metal amide, e.g. sodium amide, potassium amide and the like, an alkali metal lower alkanolate, e.g. sodium or potassium methanolate, ethanolate, n4butanolate, tertiary butanolate and the like, or any other suitable reagent, using appropriate inert solvents as diluents. A functionally converted carboxyl group as represented by R is primarily a cyano group; the salt of a functional de- I rivat'ive of a pyridyl acetic acid is, therefore, above all a salt, particularly an alkali metal salt of a pyridyl-acetonitrile having the formula:

NEC\ /Py in which Py and R have the previously-given meaning.

The reactively esterified hydroxyl group of the second reagent, as represented by X in the above Iformu'la, is primarily a hydroxyl group esterirfied with a strong inorganic acid, particularly mineral acid, e.g. hydrochloric, 'hydrobromic, hydroio'dic, sulfuric acid and the like, or a strong organic sulfonicacid, e.g. ptoluene sulfonic acid. Such group, is,therefore, aboveall a halogeno atom, e.g. chloro, bromo, iodo and the like, as well as any other analogous, reactive'ly esterified hydroxyl group. These -comopunds may be prepared, for example, by treating the corresponding phenyl-lower alkanol with an appropriate reagent capable of converting a free hydroxyl group into a reactively esteriiied hydroxyl group; a halogeno atom for example, may be introduced by treating the phenyl-lower alkanol with a thionyl halide, e.g. thionyl chloride and the like, a phosphorus halide, e.g. phosphorus rtribromide and the like, or any other suitable reagent.

.The reaction of the salt of a'cfunctiona'lly converted pyridyl-acetic acid and the reactive ester ofa phenyllower alkan-ol is carried out according to known methods, preferably in the presence of an inert solvent, for example, toluene, N,N-di-methylfiormamide and the like, and if necessary, while cooling orheating, and/or in the atmosphere of an inert gas, e.g. nitrogen.

A functionally converted carboxyl group inthe resulting starting material is converted into a free canboxyl or another functionally converted carboxyl group according to known methods. {For example, a cyano group may be converted into a carbamyl group or a free carboxyl group by hydrolysis with ,an aqueous solution of an alkali metal hydroxide, e.g. sodium hydroxide and the like. The group R is preferably a free carboxyl group, but may also stand for a functionally converted carboxyl group, such, as, for. example, carbamyl, as wellas carbolike. .and the ring closing reagent is diluted with an appropriate lower alkoxy, e.g. carhomethoxy, carbethoxy andv the like,

halogeno-carbonyl, e.g. chlorocarbonyl and the like.

The ring closure to the desired intermediate may be effected by treating the starting material with a strong Lewis acid ring closure reagent selected from the groupof Friedel-Cra-fts' reagents, such as, for. example, polyphosphoric acid, stannic chloride, aluminum chloride, sulfuric acid, hydrochloricacid, boron trifluoride and the If necessary, the mixture of the starting material inert solvent, the selection of which depends largely on the solubility properties of the starting material and the nature of the ring closing reagent; preferred inert solvents are, for example, benzene, toluene, hexane, carbon disultfide,-diethyl ether and the like. The reaction is preferably carried out at an elevated temperature, if necessary, in aclosed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen.

. In a resul -rig intermediate, which has a hydrogen attached to the carbon atom carrying the pyridyl group,

such hydrogen may be replaced by an aliphatic group; in otherwords, the groupR in the above formulae,

whenever representing hydrogen, may be replaced by an aliphatic radical R. The replacement may be carried out according to any known methods. For example, a salt,

particularly an alkali metal salt, may be formed by treating a resulting benz [b]cy-cloa1kan-'1-'one with a salt-form- 'ing, e.g alkali metal salt-formii1g reagent, such as with one of the abovementioned reagents in the presence of an appropriate inert solvent, and reacting the resulting metal, particularly alkali metal, salt with a reactive ester not an aliphatic alcohol, particularly'of a lower alkanol, ..such as an aliphatic halide, especially a lower alkyl halide,

e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, secondary @butyl chloride, bromide or iodide and the like,

or a substituted aliphatic halide, suchas a phenyl-lower alkyl halide, e.g. benzyl, l-phenylethyl or Z-phenylethyl -chloride, lbromide or iodide and the like, or any other reactive ester of an aliphatic alcohol. The introduction of an aliphatic radical may be carried out while cooling, at room temperature or :at an elevated temperature, and/ or, if necessary, in a closed vessel and/or inthe atmosphere of an inert gas, e.g. nitrogen.

The compounds of this invention may also be prepared by reacting a benz[b]cycloalkan-l-one, which has a pyridyl groupfand an aliphaticradical attached to the carbon atom adjacent to the carbonyl group, particularly a compound of the formula phosphorane. Such reagent is prepared, for example, by

reacting a tri-carbocyclic aryl-phosphine, such. as a trimonocyclic'carbocyclic ar'yl-phosphine, particularly triphenylphosphine, with a methyl ihalide, particularly a compound :of the formula CH -Hal, in which Hal is halogeno, particularly bromo, as well as chloro oriodo, and treating a resulting methyl-tri-carbocyclic aryl-phosphonium halide, such as a methyl-tri-monocyclic carbocyclic aryl-phosphonium halide, particularly 'a methyltriphenyl-phosphonium halide, with an equivalent amount of a suitable base capable of, eliminating hydrogen'halide from the methyl-tri-carbocyclic aryl-phosphonium halide,

'such as a suitable'alkali metal organic compound, for example, a lower alkyl alkali metal compound, e.g. n-butyl lithium and the. like. The preparation of the desired reagent is carried out according to known methods; the methylene-tri-carbocyclic aryl-phosphoran reagent is preferably not isolated, but can be used in solution with the inert solvent, e.g. tetrahydrofuran and the like, present during its preparation. Generally, the reagent and the benz[b]cycloalkan-1-one compound are combined at room temperature, preferably in the atmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel; if necessary, heating may be required to complete the reaction.

The starting material used in the above reaction is prepared as previously shown.

A substituent may be introduced into the carbocyclic aryl portion, e.g. the 1,2-phenylene portion, of a resulting compound. For example, upon nitration with a suitable nitrating reagent a nitro group may be introduced into the aromatic portion.

Certain substituents attached to the carbocyclic aryl portion, e.g. the 1,2-phenylene portion, of resulting compounds may be converted into other substituents. For example, a nitro group may be reduced to an amino group according to known reduction methods, for example, by controlled treatment with hydrogen in the presence of a suitable catalyst, e.g. palladium on charcoal and the like, and of an inert solvent, e.g p-dioxane and the like. An amino group may be converted into a halogeno atom by diazotization, followed by treatment with a cuprous halide according to the Sandmeyer reaction. Or, a lower alkoxy, e.g. methoxy and the like, group may be converted into a free hydroxyl group, for example, by acidic hydrolysis, such as by treatment with hydrobromic acid in the presence of acetic acid and the like.

A resulting salt may be converted into the free base, for example, by treatment with a base, such as, for example, an alkali metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide and the like, an alkali metal carbonate, e.g. lithium, sodium or potassium carbonate or hydrogen carbonate and the like, ammonia or any other suitable base, or with a hydroxyl ion exchange resin and the like.

A resulting salt may be converted into another salt according to known methods, for example, by treatment with an appropriate salt, e.g. sodium, potassium, barium, silver and the like, salt of an acid, such as of one of the above described acids, advantageously in the presence of a suitable inert solvent in which a resulting inorganic salt is preferably insoluble, or with an anion exchange preparation. r

A resulting free base may be converted into an acid addition salt thereof by reacting the former with an acid, such as one of those mentioned before, for example, by treating a solution of the base in a suitable inert solvent or solvent mixture with the acid or a solution thereof, or with an anion exchange preparation, and isolating the desired salt. Salts may be obtained in the form of their hydrates or may contain solvent of crystallization.

An N-oxide of a resulting compound may be prepared according to known methods, for example, by treatment with a peracid, particularly an organic carboxylic peracid, e.g. peracetic, perbenzoic, perphthalic acid and the like, or any other suitable peracid, as well as with other N-oxidation reagents, e.g. hydrogen peroxide and the like, preferably in an inert solvent.

The compounds of this invention may be converted into their quaternary ammonium derivatives, for example, by reaction with a reactive ester formed by a hydroxylated compound and a strong acid. Such reactive esters are, for example, those previously mentioned yielding mospheric or increased pressure, and/ or in the atmosphere of an inert gas, e.g. nitrogen. A resulting quaternary am monium compound my be converted into another quaternary ammonium compound, such as a corresponding quaternary ammonium hydroxide, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, or by treating a quaternary ammonium salt with an anion exchanger, or by electrodialysis. Other quaternary ammonium salts may be formed, for example, by treating a resulting quaternary ammonium hydroxide with an acid, such as one of those used for the preparation of acid addition salts, or with a mono-lower alkyl sulfate, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium compound may also be converted directly into another quaternary ammonium salt without the formation of the quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrochloric acid in anhydrous methanol to yield a quaternary ammonium chloride, and treatment of a quaternary ammonium salt with an anion exchange preparation may also give rise to the desired exchange of the anion portion in a quaternary ammonium salt. Quaternary ammonium compounds may also be obtained as hydrates or may contain solvent of crystallization.

The new compounds of this invention may be obtained in the form of mixtures of racemates, which mixtures may be separated into the individual racemates on the basis of physico-chemical differences, for example, by fractional crystallization, fractional distillation and the like.

Racemates of the compounds of this invention may be resolved into the optically active dand l-forms according to known procedures used for the resolution of racemic compounds. For example, the free base of a racemic d,1- compound, dissolved in an appropriate solvent or solvent mixture may be treated with one of the optically active forms of an acid containing an asymmetric carbon atom or a solution thereof. Especially useful as optically active forms of salt forming acids having an asymmetric carbon atom are D-tartaric (also l-tartaric) and L-tartaric (also d-tartaric) acid, as well as the optically active forms of malic, mandelic, camphor-lO-sulfonic, quinic, di-o-toluyltartaric acid and the like. A salt may then be isolated, which is formed by the optically active acid with one of the optically active forms of the base. From a resulting salt, the free and optically active base may be obtained according to known methods, such as outlined hereinbefore, and an optically active base may be converted into an acid addition salt, an N-oxide, a salt of an N-oxide or a quaternary ammonium compound according to the previously outlined methods. The optically active forms may also be isolated by biochemical methods.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.

Example 1 A solution of 1.0 g. of 1,2-dimethyl-2-(3-pyridyl)- 1,2,3,4-tetrahydro-naphthalen-l-ol in 15 ml. of concentrated hydrochloric acid is heated to reflux for one hour. The reaction mixture is then cooled, diluted with water, neutralized with a 40 percent aqueous solution of sodium hydroxide and the pH adjusted to 8 by adding solid sodium carbonate. The organic material is extracted three times with diethyl ether, the combined extracts are washed 11 with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The remaining yellow oil is distilled to yield the desired 2-methyl-1-methylene-2-(3-pyridyl) 1,2,3,4-tetra-. hydronaphthalene of the formula which is-collected at 115-120/0.02 mm.; yield; 0.82 g. of colorless oil.

The starting material used in the above procedure may be prepared as follows: To an ice-bath cooled solution of 25.7 g. (0.218 mol) of 3-pyridyl-acetonitrile in 150 ml. of N,N-dimethylformamide is added in small portions 10.49 g. of a 53 percent'suspension of sodium hydride in mineral oil (0.218 mol) while stirring. The mixture is agitated at room temperature until hydrogen evolution ceases and is then again cooled in an ice-bath. A solution of 40.2 g. (0.218 mol) of 2-bromoethyl-benzene in 150 ml. of toluene is added in a slow stream; the resulting mixture is stirred for three hours at room temperature'and then allowed to stand overnight at that temperature. The inorganic--material '(sodiu'm bromide) is filtered off, the filtrate is evaporated to a total volume of 100 ml., and diluted with water. The organic material is extracted with three portions of diethyl ether, the organic solutions are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and evaporated to dryness. The residue is distilled to yield'30.8 g. of a yellow oil representing 4-phenyl-2-(3-pyridyl)-butyronitrile B.P. 143-150/0.01 mm.

To a solution of 15.0 g. of 4-phenyl-2-(3-pyridyl)-butyronitrile in 60 ml. of ethanol (95 percent strength) is addeda solution of 30 g. of sodium hydroxide in 30 ml. of water, and the mixture is refluxed for 64 hours. The organic solvent is evaporated under reduced pressure, more water is added and the pH is adjusted to 5 with 2 N aqueous hydrochloric acid and aqueous acetic acid. The mixture is extracted three times with diethyl ether; the organic extracts are washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated to dryness. The acetic acid remaining in the residue is driven oil by blowing air over the surface of the oily product. 14.0 g. of 4-phenyl-2-(3-pyridyl)-butyric acid is recovered; the product melts at 106-108 and is recrystallized from a mixture of ethanol and water, M.P. 110-112.5.

11 g. of 4-phenyl-2-(3 -pyridy1)-butyric acid is stirred into 55 g. of polyphosphoric acid, preheated to 90. The temperature is elevated to 105-110" 'and maintained at that level for minutes. The resulting clear solution is stirred into icewater, the mixture is neutralized with infrared absorption spectrum shows the characteristic conjuga ted carbonyl band at 1688 cmr To a solution of 2.0 g. of 2-(3-pyridyl) 1,2,3,4-tetrahy dro-naphthalen-l-one in 25 ml. of N,N-dimethylformamide is added in small portions 0.43 g. of a 53 percent mineral oil suspension of sodium hydride While cooling in an ice-bath. The temperature is allowed to rise until the hydrogen evolution ceases; cooling is then. continued and a solution of 1.28 gJ-of methyl iodide in 15 ml. of

. 12' N,N-'dirnethylformamide is added. Cooling is discontinued, and the reactionmixture is stirred for three hours at room temperature and is then-allowed to stand overnight. Benzene is added, the solid material is'filtered off, the filtrate is evaporated to dryness andthe residue is taken up in water. -The organic material isextracted with diethyl ether, the organic solution is washed with a saturated aqueous solution of sodiumchloride and dried over sodium sulfate, filteredand evaporated. The Z-methyl-2-(3-pyridyl)-1,2,3,4-tetrahydro naphthalen-l-one is purified by distillation, B.P. 129-131/ 0.03 mm.; yield: 1.3 g. V

A Grignard reagent, prepared from 14.2 goof methyl iodide-and 2.43 g. of magnesium in 50 ml. of diethyl ether, is refluxed for one hour, after the initial exothermic reaction has subsided. After cooling to about 15, a solution of 6.0 g. of 2-methyl-2-(3-pyridyl) 1,2,3,4-tetrahydro-naphthalen-l-one in 25 ml; ofbenzene is added dropwise while stirring. The reaction mixtureis refluxed for four hours, allowed to stand at room ;-tempera ture for 16 hours, again heated to reflux for one hour and then cooled with an ice-bath, Water is added .dropwise until the milky organic layer is cleared, and a saturated aqueous solution of ammonium chloride is added. A solid material, suspended between the-organic and inorganic liquid layers, is collected, dried (yield: 1.5 g.) and recrystallized from a mixture of ethanol and water, M.P. 1905-192". The organic layer is separated, the-aqueous layer is extracted four times with ethyl acetate and the combined organic solutions are washed-with anaqueous sodium chloridesolution, dried over sodium sulfate, filtered andevaporated to dryness. 4.9 g. of a solid mate rial is recovered, which is recrystallized'from a mixture of ethanol and water, M.P. 135-148"; this material represents a mixture ofalow-melting form and the high melting form, previously isolated andmelting at 190.5-192, of 1,2-dimethyl-2-QS-pyridyl)-1,2,3,4-tetrahydronaphthalen-l-ol of the formula C 2' 7 and is used as the starting material, without further purification.

ExampleZ A mixture of 1.66 g.. of 7-chloro-1,2-dimethyl-2-(3 pyridyl)-1,2,3,4-tetrahydro-naphthalen-1-ol in'25 ml. of concentrated hydrochloric acid is refiuxedIfor minutes. The clear reaction mixture. is diluted with water, the pH is adjusted to 8-9 by adding a '50 percent solution of sodium hydroxide .in;wa'ter and crystalline sodium carb0nate.- The' organic material is extractedthree times Withdiethyl ether, the organic solution is dried over anhydrous sodium sulfate, filtered and evaporated to dryness. The residual oil crystallizesspontaneouslyto yield 1.31 g. of 7-chloro -2-methyl-1-rnethylene-l,2,3,4-tetrahydro-naphthalene of the formula which melts 83.5-85.5 after recrystallization from a mix- .ture of ethanol and-water... r

The starting material used in the abovereaction is prepared as follows: The 4-('4 chloro-phenyl)2 (3 pyridyl)- butyronitrile (B;P. 168-190/ 0.05 mm; prepared by reacting the sodium ,saltof 3-pyridyl-acetonitrile with 4- chloro-phenyl-ethyl bromide) is hydrolized; the resulting 4-(4-chloro-phenyl)-2-(3:pyridyl)-butyric acid (M.P.

13 133-135) is ring-closed with polyphosphoric acid and methylated by reacting a sodium salt of the 7-chloro-2-(3- pyridyl)-1,2,3,4-tetrahydro-naphthalen-l-one (M.P. 88- 89) with methyl iodide; these reactions are carried out according to the procedure described in Example 1.

To the cooled Grignard reagent, prepared by reacting 5.7 g. methyl iodide and 0.96 g. of magnesium turnings in 30 ml. of diethyl ether, is added dropwise a solution of 3.6 g. of 7-chloro-2-(3-pyridyl)-1,2,3,4-tetrahydronaphthalen-l-one in 20 ml. of diethyl ether while stirring. The reaction mixture is heated to reflux for two hours, then diluted with 20 ml. of benzene and again refluxed for four hours. After cooling it is poured into 100 ml. of a saturated aqueous solution of ammonium chloride; the turbid aqueous layer is separated, cleared by adding 23 ml. of glacial acetic acid and extracted twice with diethyl ether. three times with 2 N aqueous hydrochloric acid and discarded.

The aqueous solutions are made basic with crystalline sodium carbonate monohydrate and extracted five times with ethyl acetate. The combined organic extracts are washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated to dryness. The resulting gummy product is treated with diethyl ether to give 2.3 g. of a mixture of the two isomers of 7-chloro-1,2-dimethyl-2-(3-pyridyl)-1,2,3,4-tetrahydr0- naphthalen-l-ol of the formula which melts at 139-174". The mixture is recrystallized twice from a mixture of ethanol and water; the higher melting form, M.P. 201-204", analyzes correctly. The crude mixture of the two isomers is used in the following dehydration.

Other compounds prepared according to the above described procedure are, for example,

The combined ether extracts are washed I 1 4 What is claimed is:

1. A member selected from the group consisting of a compound of the formula:

.H.. R in which Ph stands for a member selected from the group consisting of 1,2-phenylene, lower alkyl-l,2-phenylene, hydroxy-1,2-phenylene, lower alkoxy-l,2-phenylene, halogeno-1,2-phenylene, nitro-1,2-phenylene and amino-1,2- phenylene, Py is pyridyl, R stands for lower alkyl, and the group of the formula (C H in which the letter It stands for a whole number from one to seven, is alkylene and separates the 1,2-phenylene Ph group from the carbon atom carrying the pyridyl group Py and the lower alkyl group R by one to three carbon atoms, acid addition salts thereof, the N-oxide thereof, acid addition salts of the N-oxide thereof and lower alkyl quaternary ammonium salts thereof.

2. A compound of the formula (6112 O Py CHa-CH R in which Ph' stands for 1,2-phenylene, Py is pyridyl, and R stands for lower alkyl.

3. The compound of the formula:

P \C/ CHFCH R in which Ph' stands for halogeno-1,2-phenylene, Py is pyridyl, and R stands for lower alkyl.

4. 2 methyl 1 methylene 2 (3 pyridyl) 1,2,3,4-

- tetrahydro-naphthalene.

5. 7 chloro 2 methyl 1 methylene 2 (3 pyridyl)-1,2,3,4-tetrahydro-naphthalene.

References Cited by the Examiner UNITED STATES PATENTS 2,921,940 1/ Ramsden 260-297 2,967,181 l/61 Herrick et al. 260-290 2,982,783 5/61 Schenck et al. 260-297 2,991,287 7/61 Fallon et al. 260-290 3,042,682 7/62 Aries 260-297 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA: 